Venetoclax + Azacitidine for Myelodysplastic Syndrome

(Verona Trial)

Recruiting at 294 trial locations

Overseen By ABBVIE CALL CENTER

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AbbVie

Must not be taking: Hypomethylating agents, Chemotherapy

Disqualifiers: Therapy-related MDS, MDS/MPN, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 36 months

531 Participants Needed

Trial Summary

What is the purpose of this trial?

Myelodysplastic Syndrome (MDS) is a group of disorders that gradually affect the ability of a person's bone marrow (semi-liquid tissue present in many bones like backbones) to produce normal blood cells. Some people with MDS have a risk of the disease progressing to acute myeloid leukemia (AML), and a risk of death from the disease itself. Symptoms of MDS include fatigue, shortness of breath, unusual paleness due to anemia (low red blood cell count), easy or unusual bruising, and red spots just beneath the skin caused by bleeding. The purpose of this study is to see how safe and effective venetoclax and azacitidine (AZA) combination are when compared to AZA and a placebo (contains no medicine), in participants with newly diagnosed higher-risk MDS. Venetoclax is an investigational drug being developed for the treatment of MDS. The study consists of two treatment arms - In one arm, participants will receive venetoclax and AZA. In another arm, participants will receive AZA and placebo. Adult participants with newly diagnosed higher-risk MDS will be enrolled. Around 500 participants will be enrolled in approximately 220 sites worldwide. Participants in one arm will receive oral doses of venetoclax tablet and intravenous (infusion in the vein) or subcutaneous (given under the skin) AZA solution. Participants in another arm will receive oral doses of placebo tablet and intravenous or subcutaneous AZA solution. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the course of the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood and bone marrow tests, checking for side effects, and completing questionnaires.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug combination Venetoclax and Azacitidine for Myelodysplastic Syndrome?

Research shows that the combination of Venetoclax and Azacitidine has been effective in treating patients with relapsed or refractory myelodysplastic syndromes, leading to improvements like complete remission and transfusion independence, with a median overall survival of 12.6 months. ^{1 2 3 4 5}

What safety data exists for Venetoclax in humans?

In a study involving Venetoclax for light-chain amyloidosis, 19% of patients experienced serious side effects, with 7% due to infections. This suggests that while Venetoclax can be effective, it may also lead to significant adverse events in some patients. ^{6 7 8 9 10}

How is the drug combination of Venetoclax and Azacitidine unique for treating myelodysplastic syndrome?

The combination of Venetoclax and Azacitidine is unique for treating myelodysplastic syndrome because it offers a new option for patients who have not responded to previous treatments, with no standard care available after failure of hypomethylating agents. This combination has shown promising results in improving survival and achieving transfusion independence in patients with relapsed or refractory myelodysplastic syndromes. ^{1 2 4 5 11}

Research Team

ABBVIE INC.

Principal Investigator

AbbVie

Eligibility Criteria

Adults newly diagnosed with higher-risk Myelodysplastic Syndrome (MDS) as per WHO criteria, with less than 20% bone marrow blasts and an ECOG status of <=2. They should not have had previous treatments for MDS or a planned stem cell transplant at the start of the study.

Inclusion Criteria

I am eligible for a stem cell transplant but do not have one scheduled.

I have been diagnosed with MDS with less than 20% bone marrow blasts.

Overall Revised International Prognostic Scoring System (IPSS-R) score > 3 (intermediate, high or very high).

Exclusion Criteria

I was previously diagnosed with a specific type of blood disorder related to previous cancer treatment or another blood condition.

I have received treatment for MDS before, including specific drugs or a stem cell transplant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax or placebo in combination with azacitidine in 28-day cycles

Up to 36 months

Regular visits at a hospital or clinic

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Treatment Details

Interventions

• Azacitidine
• Placebo
• Venetoclax

Trial Overview The trial is testing Venetoclax tablets combined with Azacitidine (AZA), against AZA with a placebo. Participants will either take Venetoclax orally and receive AZA through injection or infusion, or they'll take a placebo tablet and get AZA similarly.

Participant Groups

Group I: Arm 1: Venetoclax + Azacitidine (AZA) Experimental Treatment 2 Interventions

Participants will receive venetoclax once daily (QD) (Days 1-14) in combination with AZA QD (7 days of the first 9 days) of each 28 day cycle.

Group II: Arm 2: Placebo + Azacitidine Active Control 2 Interventions

Participants will receive placebo once daily (QD) (Days 1-14) in combination with AZA QD (7 days of the first 9 days) of each 28 day cycle.

Azacitidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

AbbVie

Lead Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

In a phase 1/2 study involving six Japanese patients aged 60 and older with acute myeloid leukaemia, the combination of venetoclax and azacitidine demonstrated a high response rate, with 83% of patients achieving a response, including three complete remissions.

The treatment was generally well tolerated, with a median overall survival of 15.7 months, although some patients experienced serious adverse events, including grade 3 fungal pneumonia, which required treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Taniguchi, S., Yamauchi, T., Choi, I., et al.[2021]

In a phase II study involving 60 older or unfit patients with newly diagnosed acute myeloid leukemia (AML), the combination of venetoclax with cladribine and low-dose cytarabine alternating with venetoclax and 5-azacitidine resulted in a high composite complete response rate of 93%.

The treatment showed promising overall survival and disease-free survival rates, with only one death occurring within 4 weeks, indicating that this regimen is effective and has a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. Kadia, TM., Reville, PK., Wang, X., et al.[2023]

In a Japanese subgroup of the phase 3 VIALE-A trial, venetoclax-azacitidine significantly improved overall survival rates compared to placebo-azacitidine, with 67% of patients alive at 12 months versus 46% in the placebo group.

The treatment also resulted in a high complete response (CR) and CR with incomplete hematologic recovery (CRi) rate of 67%, while maintaining a safety profile similar to the global study, indicating it is a viable first-line treatment for Japanese patients with acute myeloid leukemia ineligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. Yamamoto, K., Shinagawa, A., DiNardo, CD., et al.[2023]

In a phase 1b study involving 44 patients with relapsed/refractory higher-risk myelodysplastic syndromes (MDS), the combination of venetoclax and azacitidine demonstrated significant activity, with a median overall survival of 12.6 months after prior treatment failure with hypomethylating agents.

The treatment resulted in hematological improvements, including complete remission in 7% of patients and transfusion independence in 36%, indicating that venetoclax plus azacitidine can provide meaningful clinical benefits for patients with limited options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes. Zeidan, AM., Borate, U., Pollyea, DA., et al.[2023]

In a study of 13 patients with acute leukemia treated with venetoclax and azacitidine, 46% developed COVID-19, highlighting a significant risk associated with this treatment during the pandemic.

The study found that 33% of those who contracted COVID-19 died from the virus, indicating that COVID-19 can lead to severe outcomes in patients receiving AZA-VEN therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. Drozd-Sokołowska, J., Mądry, K., Barankiewicz, J., et al.[2023]

In a study of 43 patients with light-chain amyloidosis (AL) treated with venetoclax, the overall hematologic response rate was 68%, with 63% achieving very good partial response (VGPR) or complete response (CR), indicating that venetoclax is an effective treatment option for AL.

Patients with the t(11;14) genetic alteration had significantly better outcomes, with an 81% hematologic response rate and a median progression-free survival (PFS) that was not reached, compared to 40% response and a median PFS of 6.7 months for those without this alteration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis. Premkumar, VJ., Lentzsch, S., Pan, S., et al.[2021]

Irinotecan, a water-soluble analogue of camptothecin, effectively targets DNA topoisomerase I to induce cancer cell death, showing activity against various cancers including leukemia and colorectal cancer, with a dose-response relationship observed in phase I trials.

The drug's pharmacokinetics reveal significant interpatient variability, with adverse effects like neutropenia and diarrhea correlating with plasma concentrations of irinotecan and its active metabolite SN-38, highlighting the importance of monitoring these levels to optimize treatment and minimize toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics of irinotecan. Chabot, GG.[2018]

A 71-year-old patient with recurrent cervical cancer who is a compound heterozygote for UGT1A1*6 and UGT1A1*28 experienced significant hematotoxicity (grade 4 neutropenia, grade 3 anemia, and grade 4 thrombocytopenia) while receiving irinotecan hydrochloride (CPT-11) at a dose of 60 mg/m², indicating potential risks associated with this treatment in similar patients.

Despite the absence of previous case reports linking serious adverse events to CPT-11 in this genetic context, the observed severe side effects suggest that careful monitoring and dose adjustments are necessary for patients with these UGT1A1 variants undergoing combined chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent cervical cancer in a patient who was compound heterozygous for UGT1A1*6 and UGT1A1*28 presenting with serious adverse events during irinotecan hydrochloride/nedaplatin therapy. Takatori, E., Shoji, T., Miura, Y., et al.[2018]

Irinotecan (CPT-11) has demonstrated a broad range of antitumor activity across various cancer types, including lymphoma, leukemia, and several solid tumors, although most studies have focused on colorectal and gastrointestinal cancers.

Preliminary results indicate that irinotecan shows modest but reproducible activity in multiple cancers, suggesting the need for further well-designed clinical trials to better understand its efficacy and optimal use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan in lymphoma, leukemia, and breast, pancreatic, ovarian, and small-cell lung cancers. Rosen, LS.[2018]

In a rat model, combining thalidomide with irinotecan (CPT-11) significantly reduced the dose-limiting toxicities such as diarrhea and blood cell count decreases associated with CPT-11 treatment.

Thalidomide altered the pharmacokinetics of CPT-11, increasing its plasma concentration while decreasing the levels of its toxic metabolite SN-38, suggesting that thalidomide may help mitigate the harmful effects of CPT-11 through pharmacokinetic modulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic mechanisms for reduced toxicity of irinotecan by coadministered thalidomide. Yang, XX., Hu, ZP., Chan, SY., et al.[2019]

In patients with newly diagnosed unfit acute myeloid leukemia (AML), the combination of azacitidine and venetoclax is a standard first-line treatment.

However, patients with TP53-mutated AML and poor-risk cytogenetics do not benefit from adding venetoclax to azacitidine, suggesting that alternative treatment regimens should be considered for these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TP53 or Not TP53: That Is the Question. Green, SD., Zeidner, JF.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics of irinotecan. [2018]

8. Australia pubmed.ncbi.nlm.nih.gov

Recurrent cervical cancer in a patient who was compound heterozygous for UGT1A1*6 and UGT1A1*28 presenting with serious adverse events during irinotecan hydrochloride/nedaplatin therapy. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Irinotecan in lymphoma, leukemia, and breast, pancreatic, ovarian, and small-cell lung cancers. [2018]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Pharmacokinetic mechanisms for reduced toxicity of irinotecan by coadministered thalidomide. [2019]

11. United States pubmed.ncbi.nlm.nih.gov

TP53 or Not TP53: That Is the Question. [2023]